Sulfathiazole (N-2-thiazolysulfanilamide) is a highly useful product, particularly in therapeutic applications. It is a valuable antimicrobical sulfa drug and it is widely used in veterinary medicine. It is most often administered by addition to the drinking water or liquid feed of animals. For example, it is used in the drinking water for treatment of diseases of swine and poultry, and in fish tanks for treatment of tropical fish. In order to be so administered, it must be prepared in a water soluble form. Most commonly, it is administered as the water soluble sodium salt.
Sodium sulfathiazole forms a hydrate which is a solid or substantially solid solution with water. The hydrates range from the monohydrate up through and including the decahydrate. As the water content is increased, the melting point is correspondingly decreased.
Two hydrates are of particular importance in veterinary medicine. They are the pentahydrate and the sesquihydrate. The pentahydrate is specified in the British Veterinary Codex, and the sesquihydrate is the most commonly used soluble form in proprietary sulfa combinations in the United States for animal husbandry and is described in the National Formulary X.
In the preparation of the soluble form of sulfathiazole, i.e. the sodium derivative, certain problems have been encountered. In order to understand the obstacles facing the separation of soluble sodium sulfathiazole, it is helpful to review the procedure heretofore employed for its manufacture. That procedure conventionally involves dissolving sulfathiazole in a warm aqueous sodium hydroxide solution. Thereafter, the solution is cooled and filtered. The filtrate, or mother liquor, contains about ten to twenty percent of the sodium sulfathiazole. The mother liquor must be processed further in order to recover its sulfathiazole. It can be concentrated by evaporation or drying or by other conventional means so that repeated filtration will permit recovery of the sulfathiazole.
The crystalline solid collected on the filter is spread out on trays to be dried in a forced convection air drying oven or in a fluid-bed dryer. Samples are frequently taken and analyzed for their water content and depending upon the end use desired, the drying process is interrupted when the appropriate hydrate stage, e.g. the pentahydrate or sesquihydrate, is reached.
At the point at which the sulfathiazole is dissolved in the aqueous sodium hydroxide solution, problems are encountered unless the water content is maintained to a relatively large excess, i.e. at least to the equivalent of the heptahydrate. If less water is used, the solid which crystallizes is difficult to stir and solidifies to a hard cake. However, the use of such a large excess of water serves to lower the melting point such that partial melting occurs during the drying stage and that remains true even at moderate temperatures in the fluid-bed dryer, or the forced convection air drying oven. The result is that the product is not uniform and requires further processing. Moreover, it should be noted that removal of water is costly, hence an excess of water makes the process that much more uneconomical and commercially undesirable.
Another problem encountered is degradation and darkening of the product upon prolonged exposure to high concentrations of alkali at elevated temperatures. Thus, it is desirable to employ a moderate temperature and simultaneously accomplish drying within a reasonable amount of time so that the time of exposure to the alkali is minimized. An excess of water would reduce the concentration of alkali, but as noted earlier, an excess serves only to reduce the melting point and present further problems. Simply employing a lower temperature does not of itself solve the problem of degradation because lowering the temperature serves only to increase the time of drying and thus increases the exposure of the product to the alkali in the solution. Decreasing the water content which favors accelerated drying at a more moderate temperature serves, however, to increase the concentration of alkali in the solution and also presents the crystallization problem noted earlier. It also brings the melt too close to its solidification point.